Research News

How do you turn a mosquito’s genes on and off?

This microscope image shows a four-segment section of the nervous system of an Aedes aegypti mosquito embryo. The dark purple indicates areas where a gene called “short gastrulation” is being expressed. Image: Molly Duman Scheel, Indiana University School of Medicine-South Bend

By CHARLOTTE HSU

“We will focus on trying to identify regulatory sequences most useful for understanding aspects of mosquito biology that are relevant to its role as a disease vector … or that could be useful for biocontrol methods, such as genes affecting reproduction.”

Marc Halfon, professor

Department of Biochemistry

Scientists are using machine learning to identify important
sequences of DNA within the mosquito genome that regulate how the
insect’s cells develop and behave.

The research project, funded by the National Institutes of
Health (NIH), could have implications for disease control,
potentially facilitating efforts to use genetic engineering to
control mosquito populations or to create mosquitoes that have
reduced ability to transmit maladies, such as malaria, to
humans.

“Our work will break new ground in the field of mosquito
genomics and genetics,” says Marc Halfon, professor of
biochemistry in the Jacobs School of Medicine and Biomedical
Sciences. “Mosquitoes are responsible for hundreds of
thousands of deaths each year. Although we know the sequence of the
mosquito genome, we have little functional information about what
much of that genome sequence does.

“Our work will take important steps toward filling in this
crucial missing information. It will demonstrate our ability to
functionally annotate the regulatory elements within genomes of
various insect disease vectors without requiring extensive —
and expensive — new genome-scale experimental data for
each.”

The project is funded by a $449,000 grant from the National
Institute of Allergy and Infectious Diseases. It focuses on
Anopheles gambiae, an important vector for malaria
transmission.

Using machine learning to interpret the mosquito genome

Within the genome of every plant and animal, there are
regulatory switches — strings of DNA that control the
behavior of genes, dictating when and where in the body different
genes are turned on and off.

These regulatory sequences matter because they can affect a
species’ mating success and resistance to insecticides,
Halfon says. In addition, regulatory mechanisms are crucial to
genetic engineering of mosquitoes, in which researchers seek to
control the expression of foreign or mutated genes introduced in a
target animal.

For more than a decade, Halfon has worked with UB’s Center
for Computational Research to build a database called REDfly
that contains more than 5,600 regulatory sequences for a different
insect species, the fruit fly Drosophilamelanogaster. Now, his team is leveraging this trove of
information to learn more about regulatory mechanisms within the
mosquito genome.

With Saurabh Sinha, a computer scientist at the University of
Illinois at Urbana-Champaign, Halfon developed a software called
SCRMshaw that learns the regulatory sequences within REDfly, then
searches the genomes of other insects for strings of DNA with
similarities. The software has successfully identified regulatory
sequences in mosquitoes that look nothing like Drosophila
sequences to the human eye, but that possess similar traits (such
as containing a related assortment of short three- to six- letter
DNA subsequences).

“Finding regulatory elements is hard —
traditionally, it has been done by tedious experimental work that
examines one gene at a time,” Halfon says. “We wanted
to know how you can do this faster: Just by looking at a DNA
sequence, can you tell where the regulatory elements are? In at
least some cases, the answer appears to be
‘Yes.’”

Early implementation of SCRMshaw

Using SCRMshaw in mosquitoes, Halfon, Sinha and colleagues were
able to identify some of the regulatory sequences that may cause
the activity of a network of genes to shift from the midline of the
ventral nerve cord — analogous to the human spinal cord
— to the lateral regions during the formation of the embryo
of the mosquito Aedes aegypti, which transmits Zika, dengue
fever and chikungunya.

This work, published
online June 21 in the journal Developmental Biology, highlights
how SCRMshaw can pinpoint regulatory sequences in
non-Drosophila species.

“It shows how we can use SCRMshaw to address interesting
biological questions of development and evolution,” Halfon
says.

The next step is to use the new NIH funding to conduct extensive
discovery of regulatory elements within Anopheles
gambiae.

“We will focus on trying to identify regulatory sequences
most useful for understanding aspects of mosquito biology that are
relevant to its role as a disease vector — for instance,
development of the salivary glands or the midgut, or olfaction
— or that could be useful for biocontrol methods, such as
genes affecting reproduction,” Halfon says. “Once we
have generated a high-confidence set of regulatory element
predictions, we will test them in transgenic mosquitoes.”

The new NIH project is a collaboration between UB and the
University of Maryland. The effort will be bolstered by continued
development of the REDfly database, which is supported by a $1.2
million grant from the National Institute of General Medical
Sciences, part of the NIH, and a $447,000 grant from the National
Science Foundation.